Project Summary/Abstract Alcoholic liver diseases (ALD) affect over 10 million people in the world and costs more than $150 billion a year in USA. Long-term consumption of alcohol leads to various forms of liver injury including alcoholic hepatitis, fibrosis and cirrhosis, which are major causes of ALD-induced death. Ethanol (EtOH) induces various forms of cell death, which impacts the pathogenesis of ALD. Our preliminary results indicate that non-transcriptional Interferon regulatory factor 3 (Irf3) prevents ALD in mice. The ALD-preventive Irf3 mutant causes hepatocellular apoptosis during EtOH-exposure. Recently, we have uncovered a new Irf3-mediated apoptotic pathway in virus-infected cells. The apoptotic activity of Irf3 is not dependent on its function as a transcription factor. In this pathway, Irf3 is differentially activated to execute its apoptotic activity. Moreover, our preliminary results indicate that non-transcriptional Irf3 interacts with NF-?B signaling to inhibit pro-inflammatory gene expression. This led us to hypothesize that the Irf3-induced apoptotic cell death is related to its ALD-preventive function. To test our hypothesis, we have formulated two specific aims: a) investigate the specific cells in the liver that uses this pathway to prevent ALD and b) determine the biochemical mechanism of non-transcriptional Irf3-mediated apoptosis and inhibition of NF-?B activity. Successful completion of this study will elevate our knowledge on the prevention and treatment options for ALD. Based on our results, future studies will be directed to understand in-depth the molecular mechanism and specific modulators of this pathway to help prevent ALD.